Abstract Binge drinking, the consumption of five or more standard drinks for a man or four or more drinks for a woman in about a two hour period leading to intoxication, is a risky behavior practiced by17% of the U.S. population including nearly 30% of adults 18-34 years of age. Binge drinking is associated with multiple consequences and risk of progression to physical dependence on alcohol. Treatment of binge drinking includes psychosocial interventions but, overall, individuals that regularly binge drink are less likely to seek and to receive treatment. There is no FDA approved medication for binge drinking. Preclinical evidence is laying out a neurobiology of binge drinking with relevance for medication development. Recent work has shown that activating the brain melanocortin system potently reduces binge drinking in a mouse model. Furthermore, because the endogenous opioid ?-endorphin inhibits melanocortin actions, a combination of a melanocortin activator and an opioid antagonist has a synergistic effect to reduce binge drinking. This latter finding is intriguing given the recent successful clinical trial and FDA approval of Contrave? for obesity. Contrave? is a combination of bupropion (a melanocortin activator) and naltrexone (an opioid antagonist) with a target dose of 360 mg and 32 mg respectively. Therefore we hypothesize that activation of melanocortin systems +/- opioid antagonism will significantly reduce binge drinking in humans. The primary objective of the present proposal is to conduct a proof-of-concept, Phase IIa translational trial to assess for efficacy and tolerability of activating melanocortin systems +/- opioid blockade to reduce binge drinking. 60 men and women with recurrent binge drinking (at least 5 episodes a month for men and 3 for women in the prior 3 months) will be recruited and randomized to either placebo + placebo, bupropion XL 300 mg/d + placebo or bupropion XL 300 mg/d + naltrexone 50 mg/d. The trial will last 12 weeks with a 3 month follow-up to assess stability of change. Primary outcomes include frequency and intensity of binge drinking and changes in biomarkers of heavy drinking (gamma-glutamyl transferase and carbohydrate deficient transferrin) as well as adverse events. Medical Management will be provided to encourage progress towards drinking goals and to enhance retention and compliance. In summary, the present proposal is an innovative and translational clinical trial derived from exciting preclinical findings to test the hypothesis that treatment with a melanocortin activator can reduce binge drinking in humans and to test whether this action is augmented by an opioid antagonist. Evidence for an efficacy signal with good tolerability would form the foundation to conduct a well-powered Phase II/III trial. The development of an effective pharmacotherapy for binge drinking would be a significant clinical advance and one that would be expected to expand the identification and treatment of this common and highly destructive problem.